The epidermal growth factor receptor (EGFR) is a common driver molecule in non–small cell lung cancer (NSCLC), making it an attractive target for the development of novel therapies in the current era of personalized medicine. Mutations located in the EGFR tyrosine kinase domain confer increased sensitivity to tyrosine kinase inhibitors (TKIs) that attenuate EGFR activity, such as erlotinib and gefitinib. They are more common in certain patient subsets. EGFR mutations have been reported in approximately 40% of Asian NSCLC patients compared with 10% of white patients.1 Activating mutations are also more common in patients with adenocarcinoma histology, women, and people who never smoked. Two types of mutations account for 90% of sensitizing mutations in NSCLC tumors. The most common type of activating EGFR mutation—representing nearly half of thesemutations in NSCLC tumors—is in-frame deletion in exon 19 (del19), which encodes part of the kinase domain.2 The L858R point mutation in exon 21 is the second most common mutation, accounting for another 40% of EGFR mutations in NSCLC tumors.2 Uncommon mutations account for the rest.2 First-generation TKIs showed an improvement in progression-free survival (PFS) and overall response rate (ORR) over platinum-doublet chemotherapy in 7 randomized, controlled trials.3-9 However, the reversible TKIs did not improve overall survival (OS), in part because patients who failed treatment were allowed to cross over to the other treatment arm.10-16

The second-generation, ir–reversible TKI afatinib inhibits the kinase activity of the ErbB family of receptors.17 Two large, phase 3 studies compared afatinib monotherapy vs standard chemotherapy as first-line treatment for NSCLC patients with EGFR mutations. In both LUX-Lung 3, conducted worldwide, and LUX-Lung 6, conducted in Asia, afatinib demonstrated superior PFS, ORR, and patient-reported outcomes compared with chemotherapy.18,19 In the United States, afatinib is approved for first-line treatment of patients with metastatic NSCLC harboring the exon 19 deletion or the exon 21 L858R EGFR mutation. Yang and colleagues presented mature OS data on patients with these mutations from the LUX-Lung 3 and LUX-Lung 6 trials.20

Both of the trials enrolled treatment-naive patients with stage IIIB/IV adenocarcinoma of the lung as well as EGFR mutations that were detected by central laboratory testing. Patients had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Patients were stratified based on mutation type and then randomized 2:1 to receive either afatinib (400 mg daily) or up to 6 cycles of cisplatin plus either pemetrexed (in LUX-Lung 3) or gemcitabine (in LUX-Lung 6). In both studies, the primary endpoint was PFS by independent review, and OS was a secondary endpoint. LUX-Lung 3 randomized 345 patients to treatment; 62% of events had occurred at a median follow-up of 41 months. LUX-Lung 6 randomized 364 patients to treatment; 68% of events had occurred at a median follow-up of 33 months. Both arms in LUX-Lung 3 yielded a median OS of 28.2 months (hazard ratio [HR], 0.88; P=.3850). LUX-Lung 6 yielded a median OS of 23.1 months for afatinib vs 23.5 months for chemotherapy (HR, 0.93; P=.6137).

Both trials enrolled patients with the common mutations del19 and L858R, as well as uncommon mutations. The trial population reflected the incidence of mutations in the overall population: 49% to 51% of patients in each of the 4 arms had del19 tumors, 38% to 41% had the L858R mutation, and 10% to 12% had uncommon EGFR mutations. Afatinib binds with high specificity to the tyrosine kinase domain, and therefore different types of EGFR mutations may be associated with different responses to afatinib. As earlier analyses revealed, among the patients with common EGFR mutations, afatinib demonstrated a superior median PFS in both LUX-Lung 3 (13.6 months vs 6.9 months; HR, 0.47; P<.0001) and LUX-Lung 6 (11.0 months vs 5.6 months; HR, 0.25; P<.0001).18,19 The current analysis also yielded a numerically superior median OS for afatinib in LUX-Lung 3 (31.6 months vs 28.2 months; HR, 0.78; 95% CI, 0.58-1.06; P=.1090) but not in LUX-Lung 6 (23.6 months vs 23.5 months; HR, 0.83; 95% CI, 0.62-1.09; P=.1756), and neither comparison was statistically significant (Figure 1).

Subsequent treatment was the most important confounding factor. In LUX-Lung 3, 71% of patients randomized to afatinib subsequently received chemotherapy, and 75% of patients randomized to cisplatin plus pemetrexed received subsequent EGFR TKI therapy. In LUX-Lung 6, 59% of the afatinib patients later received chemotherapy, and 56% of chemotherapy patients later received an EGFR TKI. Because the studies included patients from several countries, the authors examined the influence of insurance reimbursement on subsequent treatment. In countries with universal reimbursement policies, including Japan, Taiwan, Korea, Germany, and France, 81% of patients initially on afatinib subsequently received chemotherapy, and 91% of patients initially received chemotherapy with subsequent EGFR TKI treatment. In countries without universal reimbursement policies, mainly represented by China, Thailand, Russia, the Philippines, and Malaysia, 57% of patients received afatinib followed by chemotherapy, and 52% of patients received chemotherapy followed by afatinib. However, differences in crossover did not appear to alter the superior outcome observed with afatinib. In countries with universal reimbursement policies, 91% of patients crossed over from chemotherapy to EGFR TKI therapy, and del19 was associated with an HR of 0.50 (95% CI, 0.31-0.81). In countries without universal reimbursement policies, 52% of patients received chemotherapy followed by an EGFR TKI, and del19 was associated with an HR of 0.59 (95% CI, 0.42-0.82). In Japan, 100% of patients crossed over, and del19 was associated with an HR of 0.34 (95% CI, 0.13-0.87). In contrast, the subsets of patients with L858R mutations yielded HRs greater than 1, with the lowest HR observed for Japanese patients (HR, 1.13; 95% CI, 0.40-3.21).

Dr Yang concluded that, based on the analysis of patients from these 2 large phase 3 studies, first-line afatinib significantly improved OS compared with chemotherapy in patients with the EGFR del19 mutation. The results suggest that del19 patients and L858R patients respond differently to the same EGFR TKI; therefore, these 2 patient subsets should be studied separately in the future.

Advancements in genomics have led to the identification of many predictive biomarkers in patients with NSCLC, including the EGFR mutations and ALK rearrangements. Yet targeted therapies have remained irrelevant for the majority of patients with NSCLC of squamous cell histology, and chemotherapy remains the treatment backbone. Additionally, targeted therapies are unavailable for approximately half of NSCLC patients with nonsquamous histology. In the United States, second-line therapies are associated with a median OS of approximately 7 to 8 months.1-3 In the past decade, none of the trials assessing the addition of a new agent to standard second-line chemotherapy have demonstrated an improvement in OS for patients with NSCLC. Clearly, new options are needed for patients in the second-line setting.

Angiogenesis is a critical target in NSCLC and is largely mediated by the vascular endothelial growth factor (VEGF)-A/VEGF receptor–2 axis. In order to grow beyond a few millimeters in diameter, tumors must generate their own vasculature to assimilate nutrients and remove cellular waste. Many targeted therapies have been focused on preventing the growth of tumor vasculature. Ramucirumab is a human immunoglobulin G1 monoclonal antibody that binds specifically to the extracellular domain of VEGF receptor–2, preventing its activation by all VEGF ligands. Preclinical and phase 1/2 studies demonstrated antiangiogenic and antitumor activity.4 A phase 3 study in second-line gastric cancer demonstrated that ramucirumab monotherapy can prolong OS, and ramucirumab monotherapy has been recently approved by the US Food and Drug Administration for second-line treatment of gastric cancer.5

Dr Maurice Pérol presented mature data from REVEL (A Study of Chemotherapy and Ramucirumab vs. Chemotherapy Alone in Second Line Non-Small Cell Lung Cancer Participants Who Received Prior First Line Platinum Based Chemotherapy), the first study in a decade to show an improvement in OS over standard second-line treatment for patients with metastatic NSCLC.6 The REVEL study was a double-blind, randomized, placebo-controlled, phase 3 trial assessing the impact of adding ramucirumab to docetaxel as second-line treatment for patients with stage IV NSCLC. Enrolled patients with advanced or metastatic disease had experienced disease progression during or after treatment with 1 first-line, platinum-based agent, with or without maintenance therapy. Eligibility was not predicated on specific tumor histology, and therefore enrollment included patients with squamous and nonsquamous tumor histologies. Patients with prior exposure to bevacizumab were also eligible. All patients had an ECOG performance status of 0 or 1. Exclusion criteria included major blood vessel invasion or significant intratumor cavitation, evidence of bleeding disorders, and related factors that might indicate increased sensitivity to an antiangiogenic agent.

After stratification for ECOG performance status, sex, prior maintenance therapy, and geographic region, patients were randomized in a 1:1 ratio to receive either ramucirumab (10 mg/kg) plus docetaxel (75 mg/m2) once every 3 weeks or placebo plus docetaxel at the same dosage. Treatment was continued until disease progression or toxicity. The primary endpoint was OS. Secondary endpoints included PFS, ORR, safety, and quality-of-life assessments (which will be reported at a later date). The study had a planned enrollment of 1242 patients. It required 869 events for an 85% power to detect a reduction in the risk of death with a targeted HR of 0.816 and a 2-sided α-level of less than 0.05 using the stratified log-rank test. These outcomes correspond to an increase in median OS from 7.5 months in the control arm to 9.2 months in the investigational arm.

The intent-to-treat population included 625 patients in the placebo arm and 628 in the ramucirumab-plus-docetaxel arm. Patient characteristics and baseline demographics were well balanced between the 2 arms. Patients had a median age of 62 years (range, 21-86 years), two-thirds were male, and more than 80% were white. Approximately one-fourth of patients had squamous cell histology. Wild-type EGFR was identified in one-third of patients; in the majority of patients, EGFR mutation status was unknown. Nearly one-fourth of patients had received prior taxane therapy, 14% had received prior bevacizumab, and two-thirds had benefitted from first-line platinum treatment.

The antiangiogenic treatment yielded a significant improvement in ORR over placebo (22.9% vs 13.6%; P<.001). Similarly, the disease control rate was superior (64.0% vs 52.6%; P<.001). Ramucirumab also yielded an improved median PFS over placebo (4.5 months vs 3.0 months; HR, 0.762; 95% CI, 0.677-0.859; P<.0001). In the Kaplan-Meier curve of PFS, the 2 arms separated early and remained separate for the study duration. Forest plot analysis showed a PFS benefit with ramucirumab for most subgroups, including patients with squamous histology (24% risk reduction) and those with nonsquamous histology (23% risk reduction).

The REVEL study also met its primary endpoint, showing a median OS of 10.5 months among patients who received ramucirumab plus docetaxel vs 9.1 months among those who received placebo plus docetaxel (HR, 0.857; 95% CI, 0.751-0.979; P=.0235; Figure 3). Again, the Kaplan-Meier plot showed clear separation between the 2 arms for the study duration. A Forest plot analysis of OS showed a benefit in most subgroups, particularly patients who had received prior maintenance therapy (HR, 0.69). Squamous or nonsquamous cell tumor histologies were associated with HRs of 0.88 and 0.83, respectively. Nearly half of the patients received systemic therapy after discontinuation from the study, with approximately 20% of patients receiving an EGFR TKI and the remainder receiving gemcitabine (12%), vinorelbine (10%), or pemetrexed (9%). An approximately equal proportion of patients in each arm received the same treatment after discontinuation from the study, suggesting a minimal impact on the differences in outcomes.

Among all patients who discontinued treatment, the majority did so because of progressive disease (investigational arm, 56%; placebo arm, 70%). Discontinuation owing to an adverse event (AE) was more common in the investigational arm compared with the placebo arm (15% vs 9%). More patients in the investigational arm experienced a treatment-emergent AE of grade 3 or higher (78.9% vs 71.8%); however, serious treatment-emergent AEs occurred at a similar rate in both arms (43% vs 42%, respectively). Moreover, the majority of toxicities were attributed to docetaxel. The most common grade 3/4 AEs that occurred with greater frequency in the antibody arm included neutropenia (48.8% vs 39.8%), febrile neutropenia (15.9% vs 10.0%), and fatigue (14.0% vs 10.5%); no deaths were associated with these AEs. Grade 1/2 bleeding was more frequent in the ramucirumab arm (26.5% vs 12.9%), with the majority of episodes consisting of epistaxis (18.2% for ramucirumab plus docetaxel vs 6.3% for placebo).

Antiangiogenic treatments, such as monoclonal antibodies and TKIs, have shown activity in several tumor types; however, their use is limited by their characteristic AEs, such as bleeding, thrombosis, perforation, and hypertension. Bevacizumab is the only antiangiogenic agent currently approved for treating NSCLC. Its indication is restricted to nonsquamous histology, and it is contraindicated for patients with a history of clinically significant hemorrhage or hemoptysis associated with an increased risk of bleeding.1 Nintedanib is a new oral inhibitor of angiogenesis. It blocks activation of the VEGF receptors 1 through 3, the fibroblast growth factor receptors 1 through 3, and the platelet-derived growth factor receptors α and β, leading to apoptosis of the cells in the vasculature.

LUME-Lung 1 (BIBF 1120 Plus Docetaxel as Compared to Placebo Plus Docetaxel in 2nd Line Non Small Cell Lung Cancer) is a randomized, placebo-controlled, phase 3 trial that investigated the addition of nintedanib to docetaxel in patients with advanced NSCLC after failure of first-line chemotherapy.2,3 The study enrolled 1314 patients in 27 countries with stage IIIB/IV, recurrent NSCLC that progressed after first-line chemotherapy. Patients were randomized to receive docetaxel (75 mg/m2) on day 1 plus either nintedanib (200 mg twice daily) or matching placebo on days 2 to 21 of a 3-week cycle until disease progression or unacceptable toxicity. After a median follow-up of 7.1 months, the study met its primary endpoint, showing an improved PFS among patients who received nintedanib plus docetaxel compared with those who received placebo plus docetaxel (3.4 months vs 2.7 months; HR, 0.79; 95% CI, 0.68-0.92; P=.0019). PFS improved regardless of histology. Patients with adenocarcinoma who received the nintedanib combination showed a benefit in median OS (12.6 months vs 10.3 months; HR, 0.83; 95% CI, 0.70-0.99; P=.0359).

To fully elucidate the AE profile of this new antiangiogenic drug, the incidence and intensity of antiangiogenesis-associated AEs were assessed according to the Common Terminology Criteria for Adverse Events (version 3.0) in all patients who received at least 1 dose of nintedanib, docetaxel, or placebo.3 Nongastrointestinal perforations of any grade occurred at low rates in the overall population (1.2% with nintedanib vs 0.2% with placebo), in patients with adenocarcinoma (1.3% vs 0.3%, respectively), and in patients with squamous cell carcinoma (SCC; 0.7% vs 0%, respectively). The highest rates of gastrointestinal perforation were observed in SCC patients (0.4% with nintedanib vs 1.1% with placebo). Hypertension of any grade occurred in a small proportion of patients in both arms, but was higher with nintedanib compared with placebo among the overall population (3.5% vs 0.9%, respectively), patients with adenocarcinoma (3.4% vs 0.6%, respectively), and patients with SCC (3.3% vs 0.7%, respectively; Figure 4). Bleeding events of any grade were most frequent in SCC patients and were higher with nintedanib than placebo (17.1% vs 10.8%). In contrast, patients with adenocarcinoma had similar rates of bleeding regardless of treatment (10.9% with nintedanib vs 11.1% with placebo). Among SCC patients, the most frequent bleeding events of any grade were pulmonary (10.9% with nintedanib vs 8.6% with placebo). Bleeding events of grade 3 or greater were also highest among patients with SCC in the nintedanib arm (2.9% vs 2.6% for placebo). Fatal bleeding events were rare and occurred at similar rates in the 2 treatment arms.

Although EGFR TKIs can successfully treat NSCLC, patients eventually develop resistance.1,2 In many tumor types, patients have benefitted when inhibition of driver pathways is maintained with targeted agents after disease progression. Retrospective and nonrandomized studies in NSCLC have suggested that maintenance of EGFR inhibition improves disease control over chemotherapy alone,3,4 but this approach has not been studied prospectively. Afatinib is an oral, irreversible ErbB family blocker that inhibits the EGFR/ErbB1, HER2/ErbB2, and ErbB4 receptor kinases.5,6 TKIs have demonstrated efficacy in treatment-naive NSCLC patients harboring EGFR activating mutations, as well as in patients with acquired resistance to erlotinib and gefitinib, 2 reversible EGFR TKIs.7-10

The randomized, open-label, phase 3 LUX-Lung 5 trial was designed to prospectively investigate the efficacy of afatinib plus paclitaxel in NSCLC patients who progressed after receiving at least 1 line of chemotherapy and then subsequently progressed while on afatinib.11 The trial enrolled 1154 patients from 115 centers in 23 countries. Eligible patients had stage IIIB/IV NSCLC that had failed at least 1 line of chemotherapy that included a platinum and pemetrexed. The patients had achieved a clinical benefit from erlotinib or gefitinib that lasted for at least 12 weeks but was followed
by progression.

The trial consisted of 2 parts. In part A, all patients received treatment with afatinib (50 mg daily). Patients who exhibited a complete response, partial response, or stable disease with afatinib followed by progression after 12 weeks on treatment proceeded to part B, in which they were randomized 2:1 to receive either afatinib (40 mg daily) plus paclitaxel (80 mg/m2 weekly) or the treating physician’s choice of single-agent chemotherapy.

The primary endpoint was PFS, with secondary endpoints including ORR, OS, and safety. Patients were randomized to afatinib plus paclitaxel (n=134) or chemotherapy (n=68), which consisted of paclitaxel (37%), pemetrexed (29%), docetaxel (15%), or other agents (19%). Baseline characteristics were well balanced between the 2 arms. Patients had a median age of 60 years, and half were male. More than two-thirds of patients had received at least 2 lines of prior chemotherapy, and fewer than 10% of patients had SCC.

The MET receptor tyrosine kinase is overexpressed in a subset of NSCLC tumors. Dysregulation of the MET receptor can occur through numerous mechanisms, including gene amplification; the introduction of activating mutations; and dysregulation of its ligand, hepatocyte growth factor. These aberrant events have been implicated in numerous oncogenic processes, including increased cell survival, motility, proliferation, and invasion.1 In NSCLC, MET overexpression is associated with early recurrence and a poor prognosis, even in early-stage disease.2 The combined targeting of EGFR and MET is of interest in NSCLC. Although the exact relationship between the expression, activation, and dysregulation of these 2 receptors has not been elucidated, MET and EGFR are often coexpressed in solid tumors. In lung cancer, MET increases the expression of EGFR ligands, and MET amplification has been observed in tumors with acquired resistance to EGFR TKIs.3,4

Onartuzumab is a humanized, single-arm antibody that prevents ligand binding to the MET receptor.5 In contrast, most antibodies contain 2 antigen-binding sites; when these antibodies bind to a target receptor, dimerization may occur, thus inducing activation. Onartuzumab was designed with only 1 target-binding site to prevent this potential activation of the MET pathway. A phase 2 study examined the combination of onartuzumab plus erlotinib vs erlotinib monotherapy in 137 patients with refractory NSCLC and found no difference in median PFS for the overall study population (P=.69).6 In a predefined subset analysis, however, 66 patients with MET overexpression based on immunohistochemistry (IHC) showed a significant increase in median PFS from treatment with the onartuzumab/erlotinib combination vs erlotinib alone (2.9 months vs 1.5 months; HR, 0.53; 95% CI, 0.28-0.99; P=.04). In addition, these patients showed a striking increase in median OS with the combination treatment (12.6 months vs 3.8 months; HR, 0.37; 95% CI, 0.19-0.72; P=.002). Although the onartuzumab combination was superior in patients with MET receptor overexpression by IHC, no such difference was observed for patients with MET gene amplification as assessed by fluorescence in situ hybridization.

Based on these promising phase 2 results, a larger trial was undertaken to compare the combination therapy vs erlotinib monotherapy in patients with MET overexpression. The randomized, placebo-controlled, phase 3 METLung (A Study of Onartuzumab [MetMab] in Combination With Tarceva [Erlotinib] in Patients With Met Diagnostic-Positive Non-Small Cell Lung Cancer Who Have Received Chemotherapy for Advanced or Metastatic Disease [MetLung]) trial enrolled patients with an ECOG performance status of 0 or 1 and refractory, stage IIIB or IV NSCLC of any histology with centrally confirmed MET overexpression based on IHC.7EGFR mutation status was also determined but was not a criterion for trial entry. Patients were stratified based on EGFR status (mutated vs wild-type), MET expression level (2+ vs 3+), number of prior treatments, and tumor histology. Patients were then evenly randomized to receive erlotinib (150 mg daily) plus either onartuzumab (15 mg/kg every 3 weeks) or placebo. The primary endpoint was OS; therefore, no crossover to the other treatment arm was allowed. Secondary endpoints included PFS, ORR, quality of life, safety, and pharmacokinetics. The final analysis was planned after 364 OS events, with 1 interim analysis planned after 67% of OS events had occurred. The interim analysis rejection boundaries defined superior efficacy by an HR of 0.73 or lower, with futility defined as an HR of 0.94 or greater.

The METLung study enrolled 499 patients. Patient demographics and baseline characteristics were well balanced between the 2 treatment arms. Patients had a median age of 63 years, and 56% were male. Nonsquamous tumor histology was present in 86% of patients, and nearly one-third had received 2 prior lines of therapy. MET IHC 2+ expression was reported in 79% of patients, and the remaining patients had 3+ expression. Approximately 11% of patients in each arm had a mutated EGFR.

The combination therapy was generally well tolerated. The most common AEs of any grade were rash (39% in the combination arm vs 37% with monotherapy), diarrhea (39% vs 47%, respectively), and dermatitis acneiform (32% vs 26%, respectively). AEs of any grade that were considered related to the inhibition of MET included peripheral edema (22% vs 8%, respectively) and hypoalbuminemia (17% vs 4%, respectively).

The 2014 meeting of the American Society of Clinical Oncology (ASCO) offered many important presentations on the management of patients with non–small cell lung cancer (NSCLC). Some of the most interesting studies involved third-generation epidermal growth factor receptor (EGFR) inhibitors in patients with EGFR mutations and resistance to agents such as erlotinib and gefitinib. In patients with ALK fusion proteins, a second-generation ALK inhibitor was of particular interest. Novel agents under evaluation included the antibodies necitumumab and ramucirumab in combination with standard therapies. In addition, data were presented from a trial evaluating consolidation chemotherapy in patients with stage III NSCLC.

Patients With EGFR Mutations

Dr James Chih-Hsing Yang evaluated survival outcomes in a pooled analysis of the LUX-Lung 3 and LUX-Lung 6 trials, which compared afatinib to chemotherapy.1-3 These 2 trials are the largest in this setting. The analysis showed a survival advantage in the EGFR-mutant population for afatinib vs cisplatin plus pemetrexed (in LUX-Lung 3)2 and vs cisplatin plus gemcitabine (in LUX-Lung 6).3 Interestingly, the most dramatic survival advantage was seen in patients with the EGFR exon 19 deletion, whose overall survival improved by an impressive 11 months with afatinib over chemotherapy. Unfortunately, patients with the exon 21 EGFR mutation did not show a significant improvement in median overall survival. These different survival outcomes confirm that EGFR mutations vary in their sensitivity to EGFR TKIs.

The data from this analysis reinforce the use of afatinib as first-line treatment and lend support for this agent as the “drug of choice” for those patients with an exon 19 EGFR mutation. Other tyrosine kinase inhibitors in this setting may have a similar effect, but these data advance afatinib to the forefront of these agents, particularly among patients with the EGFR exon 19 deletion mutation.

Data were presented for the phase 3 LUX-Lung 5 trial, which compared afatinib plus paclitaxel vs the investigator’s choice of chemotherapy in patients who had progressed during treatment with erlotinib/gefitinib and afatinib.4 Those patients who received the afatinib/paclitaxel combination had a significant improvement in median progression-free survival (PFS) compared with chemotherapy (5.6 months vs 2.8 months; P=.0031). However, the treatment in this trial was mostly administered in the fourth-line setting, and the results have limited applicability in clinical practice because few patients remain fit enough for fourth-line therapy.

Dr Terufumi Kato presented results from a randomized trial that evaluated the addition of bevacizumab to erlotinib vs erlotinib alone in NSCLC patients with EGFR mutations.5 The study showed an impressive difference in the primary endpoint of PFS, which nearly doubled with the addition of bevacizumab. The PFS curves separated quickly. Bevacizumab was associated with no surprising toxicities in this population of patients with EGFR mutations, who tend to be healthier than the average lung cancer patient. These data provide some optimism that PFS can be improved in this patient population. An ongoing trial is evaluating the same treatment, and results are eagerly awaited.6 The study presented by Dr Kato was relatively small (N=152), and it will be important to see if the results can be replicated. The data from the ongoing trial will also be analyzed in combination with the data from Dr Kato and colleagues.

Dr David R. Spigel presented results from the phase 3 METLung (A Study of Onartuzumab [MetMab] in Combination With Tarceva [Erlotinib]in Patients With Met Diagnostic-Positive Non-Small Cell Lung Cancer Who Have Received Chemotherapy for Advanced or Metastatic Disease [MetLung]) trial, which compared onartuzumab plus erlotinib with erlotinib alone in previously treated stage IIIb or IV NSCLC patients.7 The study failed to demonstrate a benefit from the onartuzumab combination over erlotinib monotherapy in overall survival or PFS. Subset analysis failed to identify any groups that benefited from the combination treatment. These findings are a disappointment following the promising results demonstrated in a previous phase 2 trial.8 Although the phase 2 trial showed no difference in PFS among the overall population, patients with high expression of MET seemed to derive great benefit from the addition of onartuzumab to erlotinib vs erlotinib alone; among these patients, overall survival was 12.6 months with the onartuzumab/erlotinib combination vs 3.8 months with erlotinib alone (hazard ratio [HR], 0.37; 95% CI, 0.19-0.72; P=.002). The population in the phase 3 METLung trial was enriched for patients with high expression of MET,7 and it seemed that this population had a high likelihood of benefitting from the combination of onartuzumab plus erlotinib. Unfortunately, the results of METLung were frankly negative. In fact, patients who received onartuzumab plus erlotinib were slightly disadvantaged compared with the control arm of patients who received erlotinib alone. The METLung trial is a reminder that the great test of any new agent is the phase 3 trial, and that it is possible to be misled by smaller, randomized phase 2 trials. At the ASCO presentation, there was much discussion about why the results were negative, but there is no good explanation at this time.

Novel Antibodies

Dr Nick Thatcher presented results of the SQUIRE (First-Line Treatment of Participants With Stage IV Squamous Non-Small Cell Lung Cancer With Necitumumab and Gemcitabine-Cisplatin) study, a phase 3 trial that examined the addition of necitumumab to cisplatin and gemcitabine in patients with stage IV squamous cell carcinoma NSCLC.9 Necitumumab is a fully humanized anti-EGFR antibody,10 in contrast to cetuximab, which contains approximately 30% murine protein.11 Enrollment in this trial was not based on EGFR expression. The trial met its primary endpoint by showing a statistically significant improvement in overall survival with the addition of necitumumab (11.5 months vs 9.9 months; HR, 0.84; 95% CI, 0.74-0.96; P=.01).9 This improvement in overall survival is clinically important for the population of patients with squamous cell histology. There have been no treatment advances in the squamous cell population in the past 2 decades. We have no other targeted agent offering any hope of prolonged survival, and the standard of care remains a platinum-based doublet such as carboplatin/paclitaxel and albumin-bound paclitaxel/gemcitabine.12 In contrast, patients with adenocarcinoma have options such as pemetrexed and bevacizumab, and there is also the possibility they have an actionable genotype such as the EGFR mutation or ALK translocation, which are exceedingly unusual in patients with squamous histology. The results of the SQUIRE trial offer hope for improved survival in the squamous population. Among the entire study population, the improvement in overall survival was modest, but some patients gained substantial benefit. Because necitumumab is an antibody with a specific target, there is hope that a biomarker can be developed to identify patients most likely to benefit from this agent. In the SQUIRE trial, the initial evaluation using immunohistochemistry and the H-score was not revealing. I would caution against reaching final conclusions regarding the SQUIRE trial until a more detailed analysis of the H-score data is available.

The second-line REVEL (A Study of Chemotherapy and Ramucirumab vs. Chemotherapy Alone in Second Line Non-Small Cell Lung Cancer Participants Who Received Prior First Line Platinum Based Chemotherapy) trial explored the use of the antiangiogenic antibody ramucirumab, which is an antibody to the vascular endothelial growth factor receptor 2.13,14 A key point concerning this trial is that it accepted all histologies, so patients with squamous cell carcinomas were well represented. The control arm was docetaxel, and the treatment arm consisted of ramucirumab added to docetaxel. The trial met its primary endpoint of improvement in overall survival. The addition of ramucirumab to docetaxel improved median overall survival to 10.5 months compared with 9.1 months for docetaxel alone (HR, 0.857; 95% CI, 0.751-0.979; P=.0235). Ramucirumab also improved PFS and the overall response rate. Ramucirumab is currently approved for use in gastric cancer.15 It is not known whether data from REVEL will extend the indication of ramucirumab to include use in combination with docetaxel in second-line NSCLC.

The REVEL trial is notable for several reasons. As mentioned, it accepted all NSCLC histologies. It evaluated use of an antiangiogenic agent, which is important because the only antiangiogenic agent currently approved in lung cancer is bevacizumab, which is not indicated in squamous NSCLC owing to the risk of toxicity.16 There were no toxicity concerns in the REVEL trial. In addition, monotherapy was established as second-line treatment more than a decade ago; the REVEL trial is the first to demonstrate that 2 drugs are better than 1 in the second-line setting. The REVEL trial also reinforces the concept that the angiogenic pathway is an important target, although the benefits are still modest.

The RADIANT (Randomized Double-Blind Trial in Adjuvant NSCLC With Tarceva) trial examined the use of adjuvant erlotinib vs placebo in the postsurgical setting.18 The design included early-stage patients (IB to IIIA) who were EGFR-positive according to protein expression testing using immunohistochemistry or fluorescence in situ hybridization. The use of adjuvant cisplatin-based chemotherapy was permitted. Patients were randomized in a placebo-controlled fashion. In the intent-to-treat population, the results were negative; no benefit was seen with adjuvant erlotinib vs placebo. A subset analysis of the patients with EGFR mutations (17%) showed an improvement in median disease-free survival with erlotinib vs placebo (46.4 months vs 28.5 months; P=.0391),19 although this difference was not considered statistically significant per the study protocol. Overall survival was not significantly impacted by treatment in patients with EGFR mutations.

The RADIANT trial raises some important issues. There is the temptation to treat EGFR-mutant disease in the adjuvant setting with an EGFR tyrosine kinase inhibitor, but the data for this approach are inconclusive. There does not appear to be an overall survival advantage, despite the improvement in disease-free survival. The duration of therapy in the RADIANT trial is another consideration. The intent was to deliver 2 years of therapy with erlotinib, but many patients received a shorter duration. An interesting finding of this study concerns brain recurrences, which were more frequent in the erlotinib arm than in the placebo arm (21.7% vs 17.8%, respectively). The pattern of recurrence may have therefore shifted under the influence of the EGFR tyrosine kinase inhibitor. It is important to be aware of this potential effect.

Stage III Disease

Dr Keunchil Park presented results from a phase 3 trial exploring the role of consolidation therapy after concurrent chemoradiation in patients with stage III NSCLC.20 This area is controversial. The established duration of therapy in advanced-stage disease, as well as in the adjuvant setting, is 4 cycles. In patients with stage III disease receiving induction or consolidation therapy, no survival differences have been seen with the addition of chemotherapy beyond the time of radiotherapy—or even before. The results of this trial reinforced that concept. There was no hint from the survival or PFS curves that 2 cycles of consolidation therapy, in this case with cisplatin and docetaxel, made a difference.

Although trials like this one do not necessarily change practice, they remind us that some of our routine treatment approaches are not necessarily supported by clinical trial data. One concern in this setting is that the benefit associated with administering chemotherapy beyond the chemoradiotherapy portion may be minimal, much like what is seen in the adjuvant chemotherapy setting. Four cycles of cisplatin-based therapy might be prescribed to obtain a 5% advantage at 5 years, and it took several thousand patients to statistically show that improvement.21 All of the trials in stage III disease that address this issue have ranged in size from 300 to 500 patients, so they are underpowered to show very minor differences that may be real and clinically relevant, but perhaps not statistically significant.22 Trial data from several thousand patients would be needed to show that the benefit is real and might provide a curative advantage in a small proportion of patients, much like adjuvant chemotherapy. Although Dr Park’s trial provided interesting data, it will not change clinical practice at this point.